U.S. patent application number 16/315242 was filed with the patent office on 2019-08-08 for galunisertib crystalline form, preparation method thereof and use thereof.
This patent application is currently assigned to Crystal Pharmaceutical (Suzhou) Co., Ltd.. The applicant listed for this patent is Crystal Pharmaceutical (Suzhou) Co., Ltd.. Invention is credited to Minhua Chen, Yuhao Chen, Hui Gao, Fei Lu, Xiaoyu Zhang, Yanfeng Zhang.
Application Number | 20190241572 16/315242 |
Document ID | / |
Family ID | 60912012 |
Filed Date | 2019-08-08 |
United States Patent
Application |
20190241572 |
Kind Code |
A1 |
Chen; Minhua ; et
al. |
August 8, 2019 |
GALUNISERTIB CRYSTALLINE FORM, PREPARATION METHOD THEREOF AND USE
THEREOF
Abstract
The present disclosure relates to a novel crystalline form of
Galunisertib, processes for preparation and use thereof. The
present disclosure also relates to a pharmaceutical composition
comprises the novel crystalline form of Galunisertib and use of the
novel crystalline form of Galunisertib and pharmaceutical
composition for preparing drugs treating disease. The crystalline
form of the present disclosure has good stability, solubility and
hygroscopicity, which has significant value for future drug
optimization and development. ##STR00001##
Inventors: |
Chen; Minhua; (Suzhou,
CN) ; Zhang; Yanfeng; (Suzhou, CN) ; Chen;
Yuhao; (Suzhou, CN) ; Gao; Hui; (Suzhou,
CN) ; Lu; Fei; (Suzhou, CN) ; Zhang;
Xiaoyu; (Suzhou, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Crystal Pharmaceutical (Suzhou) Co., Ltd. |
Suzhou, Jiangsu |
|
CN |
|
|
Assignee: |
Crystal Pharmaceutical (Suzhou)
Co., Ltd.
Suzhou, Jiangsu
CN
Crystal Pharmaceutical (Suzhou) Co., Ltd.
Suzhou, Jiangsu
CN
|
Family ID: |
60912012 |
Appl. No.: |
16/315242 |
Filed: |
July 21, 2017 |
PCT Filed: |
July 21, 2017 |
PCT NO: |
PCT/CN2017/092233 |
371 Date: |
January 4, 2019 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4709 20130101;
A61K 31/4162 20130101; C07D 487/04 20130101; A61P 35/00 20180101;
C07B 2200/13 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 7, 2016 |
CN |
201610533326.X |
Claims
1. A crystalline form A of Galunisertib, wherein the X-ray powder
diffraction pattern shows characteristic peaks at 2theta values of
22.0.degree..+-.0.2.degree., 10.4.degree..+-.0.2.degree. and
25.3.degree..+-.0.2.degree. using CuK.alpha. radiation.
2. The crystalline form A according to claim 1, wherein the X-ray
powder diffraction pattern shows 1 or 2 or 3 characteristic peaks
at 2theta values of 15.9.degree..+-.0.2.degree.,
14.7.degree..+-.0.2.degree. and 16.9.degree..+-.0.2.degree. using
CuK.alpha. radiation.
3. The crystalline form A according to claim 1, wherein the X-ray
powder diffraction pattern shows 1 or 2 or 3 characteristic peaks
at 2theta values of 19.5.degree..+-.0.2.degree.,
12.5.degree..+-.0.2.degree. and 20.0.degree..+-.0.2.degree. using
CuK.alpha. radiation.
4. A pharmaceutical composition, wherein said pharmaceutical
composition comprises a therapeutically effective amount of the
crystalline form A of Galunisertib according to claim 1, and
pharmaceutically acceptable carriers, diluents or excipients.
5. A method of treating myelodysplastic syndromes, comprising
administering to a patient in need thereof a therapeutically
effective amount of the crystalline form A of Galunisertib
according to claim 1.
6. A method of treating solid tumors, comprising administering to a
patient in need thereof a therapeutically effective amount of the
crystalline form A of Galunisertib according to claim 1.
Description
TECHNICAL FIELD
[0001] The present disclosure relates to the technical field of
pharmaceutical crystal technology, particularly relates to the
novel crystalline form of Galunisertib, processes for preparation
and use thereof.
BACKGROUND
[0002] Transforming growth factor-.beta. (TGF-.beta.) is a
pleiotropic cytokine with multiple tumor supporting effects,
including angiogenesis and immunosuppression. The increase of
TGF-.beta. expression is closely related to the progression of
various tumors and poor clinical prognosis. Expression of
TGF-.beta. promotes tumor growth, inhibits the immune system, and
enhances tumor spread.
[0003] Galunisertib (LY-2157299) is a TGF-.beta. kinase inhibitor
developed by Eli Lilly, which has the potential to treat
myelodysplastic syndromes and solid tumors. The chemical name of
Galunisertib is
2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrol-
o[1,2-b]pyrazole, and the structure is shown in formula I.
##STR00002##
[0004] Polymorph or polymorphism is a particular property of
certain molecule and molecular composition. Different crystalline
forms of certain compounds arise from different molecular packing
in the crystal lattice, and these crystalline forms have different
crystal structures and physical properties, such as solubility;
stability, thermal property, mechanical property, purification
capability, X-ray diffraction pattern, infrared absorption
spectroscopy, Raman spectroscopy, solid state nuclear magnetic
resonance, etc. One or more analytical techniques can be used to
distinguish different crystalline forms of the same molecule or
molecular composition.
[0005] Novel crystalline forms (including anhydrates, hydrates and
solvates) of the active pharmaceutical ingredients may offer better
processing and physicochemical properties, such as bioavailability,
stability, processability, and purification ability. Some novel
crystalline forms may serve as intermediate crystal forms to
facilitate solid state transformation to desired forms. Novel
polymorphs of raw materials provide more solid forms in the
formulation, and this can improve dissolution, improve shelf life,
and make it easier to process.
[0006] A monohydrate crystalline form of Galunisertib (designated
as Form 1 in the present disclosure) was disclosed in the patent
application WO2007018818A1, which is hereby incorporated by
reference. The X-ray powder diffraction pattern of Form 1 shows one
or more characteristic peaks at 2theta values of 9.05.degree.,
11.02.degree..+-.0.1.degree., 11.95.degree..+-.0.1.degree., and
14.84.degree..+-.0.1.degree.. However, the inventors of the present
disclosure found an anhydrous crystalline form of Galunisertib
(hereinafter referred to as Form A) during the research. The X-ray
powder diffraction pattern of Form A shows characteristic peaks at
2theta values of 22.0.degree..+-.0.2.degree.,
10.4.degree..+-.0.2.degree., and 25.3.degree..+-.0.2.degree..
Compared with the monohydrate Form 1 of the prior art, it has been
found that Form A of the present disclosure has better solubility,
hygroscopicity and stability. When Form 1 and Form A are placed in
80% RH, Form 1 is slightly hygroscopic. While Form A is
non-hygroscopic or almost non-hygroscopic. In particular, Form A
has a significant improvement in solubility compared to Form 1 of
the prior art. For example, in FaSSIF (Fasted state simulated
intestinal fluids, pH=6.5), the solubility of Form A is ten times
higher than that of Form 1 at 24 h. The increase in solubility is
beneficial to reduce drug load and improve the bioavailability of
the drug products. No form change was observed for Form A of the
present disclosure after being placed at 40.degree. C./75% RH for
one year or mechanical grinding, which indicates that Form A has
good stability. Good stability can effectively avoid crystal
transformation during drug storage and development, thus avoiding
changes in bioavailability and efficacy.
SUMMARY
[0007] In order to overcome the disadvantages of prior arts, the
main objective of the present disclosure is to provide a novel
crystalline form of Galunisertib, processes for preparation and use
thereof.
[0008] According to the objective of the present disclosure, a
novel crystalline form of Galunisertib is provided (hereinafter
referred to as Form A). The crystalline form of the present
disclosure has high solubility, is almost non-hygroscopic and has
good stability, which is suitable for industrial purification and
production. Form A provided by the present disclosure is an
anhydrite.
[0009] According to one aspect of the present disclosure, the X-ray
powder diffraction pattern of Form A shows characteristic peaks at
2theta values of 22.0.degree..+-.0.2.degree.,
10.4.degree..+-.0.2.degree. and 25.3.degree..+-.0.2.degree. using
CuK.alpha. radiation.
[0010] Furthermore, the X-ray powder diffraction pattern of Form A
shows 1 or 2 or 3 characteristic peaks at 2theta values of
15.9.degree..+-.0.2.degree., 14.7.degree..+-.0.2.degree. and
16.9.degree..+-.0.2.degree.. Preferably, the X-ray powder
diffraction pattern of Form A shows characteristic peaks at 2theta
values of 15.9.degree..+-.0.2.degree., 14.7.degree..+-.0.2.degree.
and 16.9.degree..+-.0.2.degree..
[0011] Furthermore, the X-ray powder diffraction pattern of Form A
shows 1 or 2 or 3 characteristic peaks at 2theta values of
19.5.degree..+-.0.2.degree., 12.5.degree..+-.0.2.degree. and
20.0.degree..+-.0.2.degree.. Preferably, the X-ray powder
diffraction pattern of Form A shows characteristic peaks at 2theta
values of 19.5.degree..+-.0.2.degree., 12.5.degree..+-.0.2.degree.
and 20.0.degree..+-.0.2.degree..
[0012] In a preferred embodiment, the X-ray powder diffraction
pattern of Form A shows characteristic peaks at 2theta values of
22.0.degree..+-.0.2.degree., 10.4.degree..+-.0.2.degree.,
25.3.degree..+-.0.2.degree., 15.9.degree..+-.0.2.degree.,
14.7.degree..+-.0.2.degree., 16.9.degree..+-.0.2.degree.,
19.5.degree..+-.0.2.degree., 12.5.degree..+-.0.2.degree. and
20.0.degree..+-.0.2.degree..
[0013] Without any limitation being implied, in a specific example
of the present disclosure, the X-ray powder diffraction pattern of
Form A is substantially as depicted in FIG. 1. According to the
objective of the present disclosure, a process for preparing Form A
is also provided. The process comprises: heating the solid of
Galunisertib to 170.degree. C.-240.degree. C., and the obtained
solid is Form A.
[0014] Preferably, said heating is heating to 180.degree. C.
[0015] In the present disclosure, "crystal" or "crystalline form"
refers to the crystal or the crystal form being identified by the
X-ray diffraction pattern shown herein. Those skilled in the art
are able to understand that physicochemical properties discussed
herein can be characterized, wherein the experimental errors depend
on the conditions of instruments, the sampling processes and the
purity of samples. In particular, those skilled in the art
generally know that the X-ray diffraction pattern typically vary
with the experimental conditions. It is necessary to point out
that, the relative intensity of the diffraction peaks in the X-ray
diffraction pattern may also vary with the experimental conditions;
therefore, the order of the diffraction peak intensities cannot be
the sole or decisive factor. In fact, the relative intensity of the
diffraction peaks in the X-ray powder diffraction pattern is
related to the preferred orientation of the crystals, and the
diffraction peak intensities shown herein are illustrative and not
for absolute comparison. In addition, the experimental error of the
diffraction peak position is usually 5% or less, and the error of
the position should also be taken into account, and an error of
.+-.0.2.degree. is usually allowed. In addition, due to
experimental factors such as sample thickness, the overall offset
of the diffraction peak happened, and a certain offset is usually
allowed. Thus, it will be understood by those skilled in the art
that it is unnecessary that the X-ray diffraction pattern of a
crystalline form of the present disclosure should be exactly the
same as X-ray diffraction patterns of the example shown herein. Any
crystalline forms whose X-ray diffraction patterns have the same or
similar characteristic peaks should be within the scope of the
present disclosure. Those skilled in the art can compare the
patterns shown in the present disclosure with that of an unknown
crystalline form in order to identify whether these two groups of
patterns reflect the same or different crystalline forms.
[0016] In some embodiments, crystalline Form A of the present
disclosure is pure, singular and substantially free of any other
crystalline forms. In the present disclosure, the term
"substantially free" when used to describe a novel crystalline
form, it means that the content of other crystalline forms in the
novel crystalline form is less than 20% (w/w), specifically less
than 10% (w/w), more specifically less than 5% (w/w) and further
more specifically less than 1% (w/w).
[0017] According to the objective of the present disclosure, a
pharmaceutical composition is provided;
[0018] said pharmaceutical composition comprises a therapeutically
and/or preventively effective amount of Form A and pharmaceutically
acceptable carriers, diluents or excipients.
[0019] Furthermore, Form A of the present disclosure can be used
for preparing drugs treating myelodysplastic syndromes.
[0020] Furthermore, Form A of the present disclosure can be used
for preparing drugs treating solid tumors.
[0021] Furthermore, said pharmaceutical composition may also
contain other pharmaceutically acceptable crystalline forms or
amorphous of Galunisertib or salts thereof, including but not
limited to, for example Form 1 disclosed in WO2007018818A1.
[0022] The Galunisertib Form A of the present disclosure has the
following advantages:
[0023] Good solubility. The solubility of Form A in three buffers
with different pH values is higher than that of Form 1 of the prior
art;
[0024] Good stability. No form change was observed for Form A after
being placed at 40.degree. C./75% RH for one year or mechanical
grinding. Form A has better stability than Form 1 at high
temperature.
[0025] Non-hygroscopic or almost non-hygroscopic. Compared with
Form 1 of the prior art, Form A has lower hygroscopicity. Form A is
not susceptible to high humidity to deliquescence, which is
beneficial for long-term storage of the drug.
[0026] Crystalline form with low hygroscopicity does not require
special drying conditions in the preparation process, which
simplifies the preparation and downstream process, and is easy for
industrial production. Moreover, the water content of Form A
remains substantially unchanged under different humidity
conditions, which is beneficial to the long-term storage of the
drug. Due to the non-strict requirements on storage conditions, the
cost of drug storage and quality control will be greatly reduced,
which has great economic value. Higher solubility helps to improve
the absorption and availability of drugs in the body, improve drug
efficacy and bioavailability.
BRIEF DESCRIPTION OF DRAWINGS
[0027] FIG. 1 shows an XRPD pattern of Form A in example 1.
[0028] FIG. 2 shows a DSC curve of Form A in example 1.
[0029] FIG. 3 shows a TGA curve of Form A in example 1.
[0030] FIG. 4 shows a NMR spectrum of Form A in example 1.
[0031] FIG. 5 shows a DVS plot of Form A in example 2.
[0032] FIG. 6 shows a DVS plot of Form 1 in example 2.
[0033] FIG. 7 shows the XRPD pattern overlay of Form A before and
after DVS in example 2 (top: XRPD pattern before DVS test, bottom:
XRPD pattern after DVS test).
[0034] FIG. 8 shows the XRPD pattern overlay of Form 1 before and
after DVS in example 2 (top: XRPD pattern before DVS test, bottom:
XRPD pattern after DVS test).
[0035] FIG. 9 shows the XRPD pattern overlay of Form A before and
after grinding in example 5 (top: XRPD pattern before grinding,
bottom: XRPD pattern after grinding).
[0036] FIG. 10 shows the XRPD pattern overlay of Form A before and
after stability test in example 6 (from top to bottom: the initial
Form A and samples of Form A stored at 25.degree. C./60% RH for 12
months, 40.degree. C./75% RH for 12 months, 60.degree. C./75% RH
for 2 weeks, and 80.degree. C. for 2 weeks.)
[0037] FIG. 11 shows the XRPD pattern overlay of Form 1 before and
after stability test in example 6 (from top to bottom: the initial
From 1 and Form 1 stored at 25.degree. C./60% RH for 12 months,
Form 1 stored at 40.degree. C./75% RH for 12 months, Form 1 stored
at 60.degree. C./75% RH for 2 weeks, Form 1 stored at 80.degree. C.
for 2 weeks and the initial Form A.)
DETAILED DESCRIPTION OF THE PRESENT DISCLOSURE
[0038] The present disclosure is further illustrated by the
following examples which describe the preparation and use of the
crystalline forms of the present disclosure in detail. It is
obvious to those skilled in the art that many changes in the
materials and methods can be accomplished without departing from
the scope of the present disclosure.
[0039] Instruments and methods used to collect data:
[0040] The abbreviations used in the present disclosure are
explained as follows:
[0041] XRPD: X-ray Powder Diffraction
[0042] DSC: Differential Scanning Calorimetry
[0043] TGA: Thermal Gravimetric Analysis
[0044] DVS: Dynamic Vapor Sorption
[0045] .sup.1H NMR: Proton Nuclear Magnetic Resonance
[0046] PSD: Particle Size Distribution
[0047] HPLC: High Performance Liquid Chromatography
[0048] X-ray powder diffraction pattern the present disclosure was
acquired by a Panalytical Empyrean X-ray powder diffractometer. The
parameters of the X-ray powder diffraction method of the present
disclosure were as follows:
[0049] X-ray Reflection: Cu, K.alpha.
[0050] K.alpha.1 (.ANG.): 1.540598; K.alpha.2 (.ANG.): 1.544426
[0051] K.alpha.2/K.alpha.1 intensity ration: 0.50
[0052] Voltage: 45 (kV)
[0053] Current: 40 (mA)
[0054] Scan range: from 3.0 degree to 40.0 degree
[0055] Differential scanning calorimetry (DSC) data in the present
disclosure were acquired by a TA Q2000. The parameters of the
differential scanning calorimetry (DSC) method of the present
disclosure were as follows:
[0056] Heating rate: 10.degree. C./min
[0057] Purge gas: nitrogen
[0058] Thermal gravimetric analysis (TGA) data in the present
disclosure are acquired by a TA Q5000. The parameters of the
thermal gravimetric analysis (TGA) method of the present disclosure
were as follow:
[0059] Heating rate: 10.degree. C./min
[0060] Purge gas: nitrogen
[0061] Proton nuclear magnetic resonance spectrum data (.sup.1H
NMR) was collected from a Bruker Avance II DMX 400M HZ NMR
spectrometer. 1-5 mg of sample was weighed, and dissolved in 0.5 mL
of deuterated dimethyl sulfoxide to obtain a solution with a
concentration of 2-10 mg/ML.
[0062] Unless otherwise specified, the following examples were
conducted at room temperature
[0063] The particle size distribution test in the present
disclosure is acquired by the S3500 laser particle size analyzer of
Microtrac. Microtrac S3500 is equipped with the SDC (Sample
Delivery Controller). The test is carried out by wet process, and
the dispersion medium is Isopar G. The parameters are as
follow:
TABLE-US-00001 Size distribution: Volume Run Time: 10 s Dispersion
medium: Isopar G Particle coordinates: Standard Run Number: Average
of 3 runs Fluid refractive index: 1.42 Particle Transparency: Trans
Residuals: Enabled Particle refractive index: 1.59 Flow rate: 60*
Particle shape: Irregular Filtration: Enabled *Flow rate 60% is 60%
of 65 mL/s.
[0064] Raw materials of Galunisertib used in the following examples
are prepared by known methods in the prior art, for example, the
method disclosed in WO2007018818A.
[0065] Example 1: preparation of Form A
[0066] 207.7 mg of Galunisertib solid was weighed into a 20-mL
glass vial. The glass vial was placed into an oven at 180.degree.
C. for two hours and the solid was collected.
[0067] The obtained solid in this example was confirmed to be Form
A. The X-ray powder diffraction data of the obtained solid are
shown in Table 1, while the XRPD pattern is substantially as
depicted in FIG. 1.
TABLE-US-00002 TABLE 1 2.theta. d spacing Relative intensity % 9.42
9.39 12.85 10.35 8.55 80.20 11.27 7.85 24.24 12.54 7.06 24.48 14.69
6.03 39.47 15.36 5.77 8.26 15.92 5.57 43.90 16.94 5.23 36.21 17.39
5.10 13.66 17.99 4.93 14.59 19.48 4.56 32.54 19.96 4.45 25.28 20.48
4.34 12.00 20.82 4.27 19.68 21.09 4.21 16.95 22.04 4.03 100.00
22.31 3.99 23.46 23.28 3.82 29.94 23.56 3.78 28.32 24.13 3.69 9.79
24.55 3.63 3.98 25.25 3.53 59.45 25.62 3.48 21.16 26.78 3.33 2.90
27.22 3.28 1.78 28.03 3.18 3.50 29.40 3.04 2.58 30.75 2.91 5.46
31.22 2.86 4.08 33.92 2.64 3.15 35.23 2.55 5.58 36.13 2.49 1.53
36.59 2.46 1.07 37.69 2.39 3.43 38.31 2.35 1.78 39.56 2.28 1.29
[0068] When differential scanning calorimetry (DSC) was performed
on Form A, an endothermic peak appeared with onset temperature at
around 247.degree. C., and the DSC curve is substantially as
depicted in FIG. 2.
[0069] When thermo gravimetric analysis (TGA) was performed on Form
A, about 1.8% weight loss was observed when Form A was heated to
150.degree. C., and the TGA curve is substantially as depicted in
FIG. 3.
[0070] The .sup.1H NMR spectrum of Form A is substantially as
depicted in FIG. 4, and the corresponding data are: .sup.1H NMR
(400 MHz, DMSO-d.sup.6): .delta. 8.88 (d, J=4.2 Hz, 1H), 8.25 (s,
1H), 8.12 (d, J=7.2 Hz, 1H), 8.03 (d, J=11.9 Hz, 2H), 7.58 (d,
J=3.7 Hz, 2H), 7.41 (d, J=3.4 Hz, 1H), 7.34 (s, 1H), 6.93 (s, 1H),
4.31 (s, 2H), 2.83 (s, 2H), 2.64 (s, 2H), 1.75 (s, 3H).
[0071] Example 2: Hygroscopicity of Form A
[0072] Dynamic vapor sorption (DVS) was applied to test
hygroscopicity of Form A and Form 1 disclosed in WO2007018818A1
with about 10 mg of samples. The results are listed in Table 2.
TABLE-US-00003 TABLE 2 Relative humidity (RH) Weight Weight gain at
80% gain at Crystalline form RH 95% RH Solid Form after DVS test
Form 1 0.33% 0.53% Form 1 (slightly amorphous) Form A 0.15% 0.23%
Form A (no change)
[0073] The DVS plots of Form A and Form 1 are substantially as
depicted in FIG. 5 and FIG. 6. The XRPD pattern overlay of Form A
and Form 1 before and after DVS is substantially as depicted in
FIG. 7 and FIG. 8 (top: XRPD pattern before DVS test, bottom: XRPD
pattern after DVS test).
[0074] Description and definition of hygroscopicity (Chinese
Pharmacopoeia 2015 edition, 9103 General drug hygroscopic test
guidelines, test at 25.degree. C..+-.1.degree. C., 80% RH).
[0075] Deliquescent: Sufficient water is absorbed to form a
liquid;
[0076] Very hygroscopic: Increase in mass is equal to or greater
than 15 percent;
[0077] Hygroscopic: Increase in mass is less than 15 percent and
equal to or greater than 2 percent;
[0078] Slightly hygroscopic: Increase in mass is less than 2
percent and equal to or greater than 0.2 percent.
[0079] Non-hygroscopic or almost non-hygroscopic: increase in mass
is less than 0.2%.
[0080] Weight gain of Form A at 80% RH is 0.15%. Form A is
non-hygroscopic or almost non-hygroscopic. Weight gain of Form 1 of
the prior art at 80% RH is 0.33%. Form 1 is slightly hygroscopic.
The hygroscopicity of Form A is superior to that of Form 1 of the
prior art. Form A is not susceptible to high humidity to
deliquescence.
[0081] The XRPD results show that the crystalline form of Form A of
the present disclosure does not change after DVS test and keeps
good crystallinity. After DVS test, Form A maintains stable
physicochemical properties, which is suitable for drug preparation,
storage and production process.
[0082] Example 3: Kinetic Solubility
[0083] Form A of the present disclosure and Form 1 of the prior art
were suspended into FaSSIF (Fasted state simulated intestinal
fluids, pH=6.5), FeSSIF (Fed state simulated intestinal fluids,
pH=5.0), SGF (Simulated gastric fluids, pH=1.8) and water to get
saturated solutions. After equilibrated for 1 h, 4 h and 24 h,
concentrations of the saturated solutions were measured by HPLC.
The results are listed in Table 3.
TABLE-US-00004 TABLE 3 results of kinetic solubility experiment
FaSSIF FeSSIF H.sub.2O Form Form Form Form Form Form time 1 A 1 A 1
A solubility 1 h 0.058 0.23 0.12 0.48 0.056 0.17 (mg/mL) 4 h 0.051
0.27 0.11 0.82 0.055 0.25 24 h 0.052 0.52 0.12 0.64 0.055 0.31
[0084] From the results of kinetic solubility in Table 5, the
solubility of Form A of the present disclosure is significantly
higher than that of the prior art Form 1 at each sampling point.
The solubility of Form 1 is less than 0.06 mg/mL in both FaSSIF and
H.sub.2O. The solubility of Form A of the present disclosure is 3
to 10 times higher than that of Form 1 in FaSSIF and H.sub.2O, and
4 to 8 times higher than that of Form 1 in FeSSIF, indicating that
Form A has better solubility in FaSSIF, FeSSIF and water, and Form
A has achieved unexpected effects.
[0085] Example 4: Particle Size Comparison Experiment
[0086] The results of particle size distribution are shown in table
4
TABLE-US-00005 TABLE 4 particle size distribution Solid
Ultrasonication MV form time (s) (.mu.m) D10 (.mu.m) D50 (.mu.m)
D90 (.mu.m) Form 1 0 62.25 33.41 56.97 95.11 30 45.75 24.89 42.56
68.40 60 40.41 22.40 37.88 59.87 90 37.83 20.94 35.58 55.95 Form A
0 190.8 50.28 170.3 356.4 30 116.1 34.37 106.2 210.5 60 104.1 29.37
92.81 192.2 90 91.94 26.40 83.69 167.2
[0087] The abbreviations used in the present disclosure are
explained as follows:
[0088] MV: Average particle size calculated by volume
[0089] D10: particle size which accounts for 10% of the particle
size distribution (volume distribution)
[0090] D50: particle size which accounts for 50% of the particle
size distribution (volume distribution)
[0091] D90: particle size which accounts for 90% of the particle
size distribution (volume distribution)
[0092] The results show that Form A of the present disclosure has a
larger particle size. An increase in particle size in the
production process is beneficial for product separation, filtration
and purification.
[0093] Example 5: Mechanical Stability
[0094] Solid sample of Form A of the present disclosure was ground
manually for 5 minutes in mortar.
[0095] The XRPD pattern overlay of the solids before and after
grinding is substantially as depicted in FIG. 9 (top: XRPD pattern
before grinding, bottom: XRPD pattern after grinding). The XRPD
pattern doesn't change significantly before and after grinding,
indicating that Form A can maintain stable physicochemical
properties under certain mechanical stress.
[0096] Example 6: Long-Term and Accelerated Stability
[0097] Solid samples of Form A and Form 1 were stored under
different conditions of 25.degree. C./60% RH, 40.degree. C./75% RH.
60.degree. C./75% RH and 80.degree. C. The results are shown in
Table 5
TABLE-US-00006 TABLE 5 stability experiment results Initial form
Conditions Time Solid form Form 1 25.degree. C./60% RH 12 months
Form 1 40.degree. C./75% RH 12 months Form 1 60.degree. C./75% RH 2
weeks Form 1 80.degree. C. 2 weeks Form 1 + Form A Form A
25.degree. C./60% RH 12 months Form A 40.degree. C./75% RH 12
months Form A 60.degree. C./75% RH 2 weeks Form A 80.degree. C. 2
weeks Form A
[0098] The results show that form A keeps stable for at least 12
months at 25.degree. C./60% RH and 40.degree. C./75% RH, at least 2
weeks at 60.degree. C./75% RH and 80.degree. C., indicating that
Form A has good stability at room temperature/high
temperature/high. humidity conditions. However, the stability of
Form 1 at high temperature is poor. Form 1 partially converts to
Form A after being stored at 80.degree. C. for two weeks. The XRPD
overlays of Form A and Form 1 under different conditions are
substantially as depicted in FIG. 10 and FIG. 11, respectively.
[0099] The examples described above are only for illustrating the
technical concepts and features of the present disclosure, and
intended to make those skilled in the art being able to understand
the present disclosure and thereby implement it, and should not be
concluded to limit the protective scope of this disclosure. Any
equivalent variations or modifications according to the spirit of
the present disclosure should be covered by the protective scope of
the present disclosure
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